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J. Exp. Med.,
Volume 187, Number 6, March 16, 1998 903-915
By
From the Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical
School, Boston, Massachusetts 02215
Circulating leukocytes are thought to extravasate from venules through open interendothelial
junctions. To test this paradigm, we injected N-formyl-methionyl-leucyl-phenylalanine
(FMLP) intradermally in guinea pigs, harvesting tissue at 5-60 min. At FMLP-injected sites,
venular endothelium developed increased surface wrinkling and variation in thickness. Marginating neutrophils formed contacts with endothelial cells and with other neutrophils, sometimes
forming chains of linked leukocytes. Adherent neutrophils projected cytoplasmic processes into
the underlying endothelium, especially at points of endothelial thinning. To determine the
pathway by which neutrophils transmigrated endothelium, we prepared 27 sets of serial electron microscopic sections. Eleven of these encompassed in their entirety openings through
which individual neutrophils traversed venular endothelium; in 10 of the 11 sets, neutrophils
followed an entirely transendothelial cell course unrelated to interendothelial junctions, findings that were confirmed by computer-assisted three-dimensional reconstructions. Having
crossed endothelium, neutrophils often paused before crossing the basal lamina and underlying
pericytes that they also commonly traversed by a transcellular pathway. Thus, in response to
FMLP, neutrophils emigrated from cutaneous venules by a transcellular route through both endothelial cells and pericytes. It remains to be determined whether these results can be extended
to other inflammatory cells or stimuli or to other vascular beds.
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